1. Field of the Invention
The present invention relates generally to the crystallization of drug substances and, more particularly, relates to methods and devices for crystallization by controlled evaporation.
2. Description of the Related Art
High quality crystals are used in a variety of studies throughout the process of developing a drug. In early development, solid forms of lead compounds are available in fairly small quantities. These solid forms are studied to determine which forms are most suitable to move forward in development. In late development, a well-characterized form is selected for large scale manufacturing.
Crystals are typically grown by dissolving the drug substance in a suitable solvent, then evaporating the solvent. In a conventional, manual process for forming crystals, a scintillation vial is partially filled with the drug and solvent solution and capped with aluminum foil. A small hole is poked in the foil. The vial then sits for some length of time. The slow evaporation of the solvent through the small hole in the foil favors crystal growth. There are many disadvantages, however, to the conventional method. The lack of controls for making the hole, and therefore the lack of consistency in hole size, leads to widely varying rates of evaporation, even for the same drug substance and solvent. Experimental reproducibility is thus a serious challenge. Further, the method cannot be scaled for use in small sample volumes, because the holes in the aluminum foil are no longer “small,” relatively speaking, when the sample volume is reduced to that of a well in a 96-well plate. In fact, in sample volumes below 0.5 mL, evaporation using holes poked in aluminum foil is generally too fast to permit formation of high quality crystals. The problem of rapid evaporation is particularly severe when the solvent is very volatile.
Current instruments that automate the process of crystal formation also suffer significant drawbacks. One device, for example, feeds inert gas close to the surface of the wells in a 96-well plate using a manifold with a common exhaust. This allows for controlled evaporation, however, only if the wells are filled with one solvent or multiple solvents of similar volatilities. Thus, among other disadvantages, current designs cannot accomplish controlled evaporation of multiple solvents of dissimilar volatilities simultaneously. Thus, slow, controlled evaporation of multiple solvents of varying volatilities from small volume wells of, for example, a 96-well plate, remains a significant challenge in the creation of high quality crystals.